Interfering with protein-protein interactions or protein-nucleic acid interactions have been regarded as daunting goals in drug discovery. Major strides have been made the last decade in developing small molecule agents to target protein-protein interactions. However, regulation of protein-RNA interactions lags behind, primarily due to the fact that RNA molecules pose a particular challenge with their high flexibility. RNA-binding proteins (RBPs) play key roles in post-transcriptional modifications, which, along with transcriptional regulation, is believed to be a main method of controlling patterns of gene expression during development.
Toll-like receptors (TLRs) are highly conserved transmembrane proteins that detect pathogen-associated molecular patterns and elicit pathogen-specific immune responses. Thirteen homologous human TLRs have been reported to date. The ligands for these receptors are highly conserved microbial molecules such as lipopolysaccharides (LPS) (recognized by TLR4), lipopeptides (TLR2 in combination with TLR1 or TLR6), flagellin (TLR5), single-stranded RNA (TLR7 and TLR8), double stranded RNA (TLR3), CpG motif-containing DNA (recognized by TLR9), and profilin present on uropathogenic bacteria (TLR11). TLR3 signaling is activated by dsRNA released from necrotic cells during inflammation or viral infection. TLR3 activation induces secretion of type I interferons and pro-inflammatory cytokines, such as the NF-κB-dependent genes, TNF-α, IL-1, and IL-6 and triggers immune cell activation and recruitment that are protective during certain microbial infections. A dominant-negative TLR3 allele has been associated with increased susceptibility to herpes simplex encephalitis, a serious illness with significant risks of morbidity and death, upon primary infection with HSV-1 in childhood. In mice, TLR3 deficiency is associated with decreased survival upon coxsackie virus challenge. In addition, uncontrolled or sustained innate immune response via TLR3 has been shown to contribute to morbidity and mortality in certain viral infection models including West Nile, phlebovirus, vaccinia, and influenza A. TLR3 has also been implicated to be involved with diseases such as atherosclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Thus, modulation of TLR3 pathways offers an attractive method to fight a variety of diseases.
Despite this potential, the discovery of treatment agents has been slow due to the complexity associated with disrupting the protein-RNA contact: immense effort is required to design individual compounds that target specific RNA-binding domains with high binding affinity, selectivity, and also functional activity in cell-based assays. Nevertheless, the information gained with regards to the residues involved in protein-RNA interactions could enable the development of specific agents to disrupt these interactions and thereby limit their signaling capacity.
Therefore, there is a need for compounds that can modulate TLR3. There is also a need for compounds that can modulate TLR3/dsRNA interaction.